Stable anti-PD-1 antibody drug formulations

Abstract

To provide a stable anti-PD-1 antibody pharmaceutical formulation. [Solution] A stable anti-PD-1 antibody pharmaceutical formulation is provided, comprising (a) an anti-PD-1 antibody or its antigen-binding fragment, (b) a stabilizer, and (c) a buffer, free of surfactants, and having a pH of approximately 4.5 to 6.5.

Description

[Technical Field]

[0001] The present invention relates to a stable anti-PD-1 antibody pharmaceutical formulation and a method for producing the same. [Background technology]

[0002] There is a growing need to develop stable anti-PD-1 antibody drug formulations to enhance drug stability. It's been exposed. Anti-PD-1 antibody pharmaceutical preparations contain buffers, stabilizers, and for drug stability. It contains surfactants.

[0003] However, surfactants like polysorbate are broken down through oxidation and hydrolysis. It is known that this results in reactive oxygen species (ROS) This generates ecies, causing oxidative damage to antibody proteins.

[0004] Therefore, it contains surfactants that may affect the stability of anti-PD-1 antibody pharmaceutical formulations. First, there is still a need for the development of formulations that can stabilize antibody proteins. ru. [Overview of the project] [Problems that the invention aims to solve]

[0005] The problems that the present invention aims to solve are (a) an anti-PD-1 antibody or its antigen-binding fragment; ( b) Stabilizer; and (c) Buffering agent; free of surfactants; pH 4.5 to 6. The objective is to provide a stable anti-PD-1 antibody pharmaceutical formulation containing 5.

[0006] The problem that the present invention aims to solve is also the step of administering the aforementioned pharmaceutical preparation to an individual. This includes providing a method for treating cancer in an individual.

[0007] The problem that the present invention aims to solve is to provide a method for producing the aforementioned pharmaceutical preparation. That is the case. [Means for solving the problem]

[0008] All technical terms used herein are defined in relation to the present invention unless otherwise specified. In the field, it is used in the sense that is generally understood by those skilled in the art. Furthermore, this specification includes: The preferred methods and samples are described, but similar or equivalent methods may also be included. , falls within the scope of the present invention. Furthermore, the numerical values ​​described herein, unless explicitly stated, It is considered to include the meaning of "about". Of all the publications listed as references in this specification The content is integrated as a whole in this specification by reference.

[0009] One embodiment includes (a) an anti-PD-1 antibody or its antigen-binding fragment; (b) a stabilizer; and (c A stable anti-PD agent containing a buffer, free of surfactants, and with a pH of 4.5 to 6.5. -1 We provide antibody-pharmaceutical formulations.

[0010] Unlike commonly known antibody-containing pharmaceutical preparations, the aforementioned pharmaceutical preparation is a surfactant. Although it does not contain [specific ingredient], it provides a desirable environment for storing anti-PD-1 antibodies and maintains their stability. This is possible. The pH of the pharmaceutical preparation is, for example, pH 4.5 to 6.5, pH 4.5 pH 4.8 to 6.3, pH 5 to 6.3, pH 5.2 to 6.3 pH 4.5 to 6.0, pH 4.8 to 6.0, pH 5.0 to 6.0, pH 5 pH 0.2 to 6.0, pH 4.5 to 5.8, pH 4.8 to 5.8, pH 5.0 or less 5.8, pH 5.2 to 5.8, pH 4.5 to 5.6, pH 4.8 to 5.6 , pH 5.0 to 5.6, pH 5.2 to 5.6, pH 4.9 to 5.5, pH 4 .9, pH 5.0, pH 5.1, pH 5.2, pH 5.3, pH 5.4, or pH 5 .5 as well.

[0011] The term "antibody" refers to any form of antibody having the activity of specifically binding to PD-1. The said antibody includes monoclonal antibodies, polyclonal antibodies, humanized antibodies, human antibodies, and chimeric antibodies. The said antibody is also the pembrolizumab monoclonal antibody.

[0012] When it is stated that the pharmaceutical formulation provided herein "does not contain Component A", it may mean that the said pharmaceutical formulation does not contain Component A or contains it substantially not. "Substantially not containing Component A" means either not containing Component A at all or, even if Component A is present, it is present in a trace amount that does not substantially affect the properties of the pharmaceutical formulation or is present in an undetectable amount, and this is also interpreted to include such cases.

[0013] The term "antigen-binding fragment" is a fragment in an anti-PD-1 antibody that can bind to the PD-1 antigen and includes, for example, Fab fragments, F(ab’)2 fragments, Fc fragments, or scFv fragments.

[0014] The "pembrolizumab antibody" is a humanized antibody used in cancer immunotherapy and is one of various trade names, known as Keytruda(R). It will be sold under the name [name]. Pembrolizumab is used to treat melanoma and non-small cell lung cancer (NS). Lung cancer, including non-small cell lung cancer (CLC), head and neck squamous cell carcinoma (HNSCC) Head and neck cancers, including adrenal and neck squamous cell cancer, and typical Hodgkin lymphoma (cHL). Hodgkin lymphoma (including classical Hodgkin lymphoma), urothelial carcinoma, renal cell carcinoma, gastric cancer High-frequency microsatellite instability cancer (MSI-H) h) cancer, deficient mismatch repair (dMMR) solid tumors, It is also used for cervical cancer, liver cancer, Merkel cell carcinoma (MCC), etc. The pembrolizumab antibody is also used in commercially available Keytruda(R). A "biosimilar" or "bi" of the active pembrolizumab antibody present in the body. It also contains "biobetter". This pembrolizumab antibody is SEQ ID NO: 1 Heavy chain CDR1 having the amino acid sequence of SEQ ID NO: 2, and heavy chain CDR2 having the amino acid sequence of SEQ ID NO: 2 , and heavy chain CDR3 having the amino acid sequence of SEQ ID NO: 3, and the amino acid sequence of SEQ ID NO: 4 Light chain CDR1 having a column, light chain CDR2 having the amino acid sequence of sequence number 5, and sequence number This also contains a light chain CDR3 having the amino acid sequence of type 6. This includes a heavy chain variable region having the amino acid sequence of SEQ ID NO: 7, and the amino acid sequence of SEQ ID NO: 8. It also includes a variable light chain region.

[0015] Pembrolizumab is a programmed cell death protein 1 (PD-1:pr It targets the grammed cell death protein 1) receptor. Pembrolizumab targets cancer cells IgG4 isotype antibodies that block the protective mechanism, causing the immune system to destroy cancer cells. Pembrolizumab was approved for medical use in the United States in 2014. Furthermore, in 2017, pembrolizumab was found to be effective for specific genetic abnormalities (anomalies), such as misdiagnosis. It exhibits mismatch repair deficiency or microsatellite instability. For unresectable or metastatic solid tumors, this procedure is permitted. Furthermore, pembrolizumab can be used alone or in combination with other chemotherapy agents. The pembrolizumab is also administered by intravenous or subcutaneous injection.

[0016] The pembrolizumab can also be produced by common methods known in the industry. For example, US9,834,605 ​​and WO2008 / 156712A1 are used by persons skilled in the art in the industry. This document describes methods that can be used to produce mubrolizumab antibodies. The law is incorporated herein by reference. For example, the pembrolizumab is in the host cell It can also be produced by recombinant expression of immunoglobulin light chain genes and immunoglobulin heavy chain genes. To be created.

[0017] The concentration of the anti-PD-1 antibody, for example, pembrolizumab antibody or its antigen-binding fragment, is Furthermore, the aforementioned anti-PD-1 antibody, for example, pembrolizumab The concentration of the antibody or its antigen-binding fragment is determined considering the stability and viscosity of the pharmaceutical formulation. The following are also selected: the anti-PD-1 antibody, for example, pembrolizumab antibody or its antigen binding. The concentration of the fragments is, for example, 5 to 300 mg / mL, 5 to 250 mg / mL, or 5. 200 mg / mL, 10 to 200 mg / mL, 10 to 165 mg / mL, 15 or 160 mg / mL, 5 to 45 mg / mL, 10 to 40 mg / mL, 15 Ishi 35 mg / mL, 20 to 30 mg / mL, 130 to 170 mg / mL, 13 5 to 165 mg / mL, 140 to 160 mg / mL, 145 to 155 mg / mL, approximately 25 mg / ml, or approximately 150 mg / ml. The aforementioned anti-PD-1 antibody, e.g. For example, pembrolizumab antibody or its antigen-binding fragment is pharmaceutically produced at the aforementioned concentration. It can contribute to the stability of the drug and the maintenance of viscosity and pH of pharmaceutical formulations suitable for administration.

[0018] The stabilizer is selected from the group consisting of polyols, amino acids, and metal salts. One or more have been selected. In this specification, the term "polyol" refers to multiple individuals. The polyol is shown as an excipient having multiple hydroxyl groups. This also includes sugars, sugar alcohols, and sugar acids. The sugars are soluble carbon The sugar is a hydrated product. The sugar may also be a monosaccharide, disaccharide, oligosaccharide, or polysaccharide. Kohl is an organic compound derived from sugar, where each carbon atom has one hydroxyl group. The sugar acid has a sugar having a carboxylic acid group on one or both of its chains. The term "ol" includes the anhydrous or hydrated form of polyols. For example, trehalose is a polyol. It contains not only trehalose but also trehalose dihydrate.

[0019] The polyol is glucose, fructose, mannose, galactose, sucrose. Sodium, lactose, maltose, trehalose, mannitol, sorbitol and polyethylene It is also one or more selected from the group consisting of lenglycol. The polyol is so Rubitol, sucrose, trehalose, mannose, maltose, mannitol, also It is also a mixture of those. The concentration of the polyol in the pharmaceutical formulation is anti-P Stability and pharmaceutics of D-1 antibodies, such as pembrolizumab antibodies or their antigen-binding fragments. It can be freely adjusted within a range desirable to maintain the viscosity of the target formulation, and each specific The properties also vary individually depending on the type of polyol, sugar alcohol, or sugar acid.

[0020] The aforementioned sugars are present in concentrations of 1.0 to 15.0% (w / v), 3.0 to 15.0% (w / v), 5.0 to 15.0% (w / v), 7.0 to 15.0% (w / v), 1.0 to 10.0% (w / v), 3.0 to 10.0% (w / v), 4.0 to 10.0% ( w / v), 5.0 to 10.0% (w / v), 7.0 to 10.0% (w / v), 1 0.0 to 7.0% (w / v), 2.0 to 7.0% (w / v), 3.0 to 7.0 %(w / v), 4.0 to 7.0%(w / v), 1.0 to 5.0%(w / v), 2 0.0 to 5.0% (w / v), 3.0 to 5.0% (w / v), or 4.0 to 5.0% (w / v), 4.5 to 5.0% (w / v) (e.g., approximately 4.7% (w / v)), 6.5 to 8.5% (w / v) (e.g., approximately 6.8% (w / v), approximately 7.0% (w / v)) Approximately 7.2% (w / v), or 7.8 to 8.2% (w / v) (Example: Approximately 7.8% (w (w / v), approximately 7.9% (w / v), approximately 8.0% (w / v), approximately 8.1% (w / v), or approximately It is also 8.2% (w / v). The aforementioned sugars are, for example, sucrose, glucose, galactose. It is also maltose, protose, trehalose, or a mixture thereof.

[0021] The concentration of the sugar alcohol is 1.0 to 20.0 w / v%, for example, 1.0 to 1 5.0 w / v%, 1.0 to 10.0 w / v%, 2.5 to 10.0 w / v%, 3. 0 to 10.0 w / v%, 3.5 to 10.0 w / v%, 4.0 to 10.0 w / v%, 1.0 to 8.0 w / v%, 2.5 to 8.0 w / v%, 3.0 to 8.0 w / v%, 3.5 to 8.0 w / v%, 4.0 to 8.0 w / v%, 1.0 to 6 0.0 w / v%, 2.5 to 6.0 w / v%, 3.0 to 6.0 w / v%, 3.5% or less 6.0 w / v%, 4.0 to 6.0 w / v%, 4.0 to 5.5 w / v%, or It is also 4.0 to 5.0 w / v%. The sugar alcohol is, for example, sorbitol, ma It is also nitrol, its hydrate, or a mixture thereof.

[0022] The aforementioned amino acids are glycine, alanine, valine, leucine, isoleucine, proline, Phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, meth Onion, asparagine, glutamine, lysine, arginine, histidine, aspartic acid , glutamic acid, a pharmaceutically acceptable salt thereof, or a mixture thereof. Mino acids include, for example, glycine, proline, phenylalanine, tyrosine, and tryptophan. This may also include lysine, arginine, their pharmaceutically acceptable salts, or mixtures thereof.

[0023] As the aforementioned stabilizer, the concentration of the amino acid is 0.1 to 300.0 mM, 0.5 to 300.0 mM, 1.0 to 300.0 mM, 5.0 to 300.0 mM, 10.0 or 300.0 mM, 25.0 or 300.0 mM, 30.0 or 300.0 mM 50.0 to 300.0 mM, 80.0 to 300.0 mM, 100.0 to 3 0.0 mM, 120.0 to 300.0 mM, 0.1 to 250.0 mM, 0.5 or 250.0 mM, 1.0 or 250.0 mM, 5.0 or 250.0 mM, 1 0.0 to 250.0 mM, 25.0 to 250.0 mM, 30.0 to 250. 0 mM, 50.0 to 250.0 mM, 80.0 to 250.0 mM, 100.0 mM Stone 250.0 mM, 120.0 to 250.0 mM, 0.1 to 200.0 mM, 0.5 to 200.0 mM, 1.0 to 200.0 mM, 5.0 to 200.0 mM M, 10.0 to 200.0 mM, 25.0 to 200.0 mM, 30.0 to 2 0.0 mM, 50.0 to 200.0 mM, 80.0 to 200.0 mM, 100 0.0 to 200.0 mM, 120.0 to 200.0 mM, 0.1 to 160.0 mM, 0.5 to 160.0 mM, 1.0 to 160.0 mM, 5.0 to 160 0.0 mM, 10.0 to 160.0 mM, 25.0 to 160.0 mM, 30.0 mM Stone 160.0 mM, 50.0 to 160.0 mM, 80.0 to 160.0 mM, 100.0 to 160.0 mM, 120.0 to 160.0 mM, 130.0 to 150.0 mM, 0.1 to 100.0 mM, 0.5 to 100.0 mM, 1.0 Stone 100.0 mM, 5.0 to 100.0 mM, 10.0 to 100.0 mM, 2 5.0 to 100.0 mM, 30.0 to 100.0 mM, 50.0 to 100. 0 mM, 80.0 to 100.0 mM, 0.1 to 50.0 mM, 0.5 to 50 0.0 mM, 1.0 to 50.0 mM, 5.0 to 50.0 mM, 10.0 to 50 0.0 mM, 25.0 to 50.0 mM, or 30.0 to 50.0 mM, 0.1 Stone 40.0 mM, 0.5 to 40.0 mM, 1.0 to 40.0 mM, 5.0 mM or less 40.0 mM, 10.0 to 40.0 mM, 25.0 to 40.0 mM, or 3 0.0 to 40.0 mM, 0.1 to 30.0 mM, 0.5 to 30.0 mM, 1 0.0 to 30.0 mM, 5.0 to 30.0 mM, 10.0 to 30.0 mM, 2 5.0 to 30.0 mM, 0.1 to 20.0 mM, 0.5 to 20.0 mM, 1 0 to 20.0 mM, 5.0 to 20.0 mM, 10.0 to 20.0 mM, 0 0.1 to 10.0 mM, 0.5 to 10.0 mM, 1.0 to 10.0 mM, and It is also 5.0 to 10.0 mM. In one specific example, the amino acid is 17 to 29 mM arginine, its pharmaceutically acceptable salt, or a mixture thereof. In one specific example, the amino acid is 24 to 29 mM glycine, which is pharmaceutically acceptable. It is also a tolerable salt, or a mixture thereof. The concentration of the amino acid is the target of the pharmaceutical preparation. Without affecting the target pH, anti-PD-1 antibodies, such as pembrolizumab antibodies or The antigen-binding fragment is freely regulated within a range that does not affect its stability, and each It also varies individually depending on the specific amino acid.

[0024] The aforementioned metal salts are NaCl, KCl, NaF, KBr, NaBr, Na2SO4, and NaS It can also be CN, CaCl2, MgCl2, or K2SO4. The metal salt is, for example, Na It is also Cl or Na2SO4. The concentration of the metal salt is 1.0 to 300.0 mM. 5.0 to 150.0 mM, 10.0 to 150.0 mM, 30.0 to 150. 0 mM, 50.0 to 150.0 mM, 80.0 to 150.0 mM, 100.0 mM Stone 150.0 mM, 120.0 to 150.0 mM, 5.0 to 125.0 mM, 10.0 to 125.0 mM, 30.0 to 125.0 mM, 50.0 to 125 0.0 mM, 80.0 to 125.0 mM, 100.0 to 125.0 mM, 120. 0 to 125.0 mM, 5.0 to 100.0 mM, 10.0 to 100.0 mM 30.0 to 100.0 mM, 50.0 to 100.0 mM, 80.0 to 10 0.0 mM, 5 to 80.0 mM, 10.0 to 80.0 mM, 30.0 to 80 It can be 0.0 mM, or 50.0 to 80.0 mM. In one specific example, the metal salt This ranges from 5.0 to 150.0 mM, 20.0 to 140.0 mM, or approximately 100.0 It is also sodium chloride in mM. The concentration of the metal salt in the pharmaceutical formulation of the present invention is anti Maintaining the stability of PD-1 antibodies, such as pembrolizumab antibodies or their antigen-binding fragments. It is freely adjusted within the range that does not cause precipitation, and each specific metal salt However, it varies from person to person.

[0025] In this specification, the term "buffer" refers to a substance that provides a pharmaceutical formulation with resistance to pH changes. The composition is shown in which the buffering agent is added in such a manner. The buffering agent, within an acceptable range, affects the p of the formulation. H can be maintained. The buffering agent generally has an acid-base pair (conjugate) component. Through the action of the above formulation, the formulation is made resistant to pH changes. In this specification, the buffer If a concentration is mentioned, the mentioned concentration refers to the free acid or free base form of the buffer. This indicates the molar concentration of the state.

[0026] In one specific example, the buffering agent is a buffering agent having buffering capacity. It is also one or more selected types. The buffering agent is, for example, phosphoric acid, acetic acid, citric acid, succinic acid, carbonic acid, amino acids, their ionized forms, and their pharmaceutical properties It is also one or more selected from the group consisting of acceptable salts. It is also histidine. The concentration of this amino acid does not affect the pH of the liquid formulation of the present invention. Furthermore, it can be freely adjusted within a range that does not affect the stability of the antibody or its antigen-binding fragment. Furthermore, it differs individually depending on the specific amino acid. The salt is an alkali metal It is also a salt or hydrochloride salt. The alkali metal is also sodium or potassium.

[0027] The buffering agent is phosphoric acid, acetic acid, citric acid, succinic acid, carbonate, histidine, and its ionized form. One or more selected from the group consisting of the modified form and its pharmaceutically acceptable salts. There are also others.

[0028] In other specific examples, the buffering agent is acetic acid, acetate, succinic acid, succinate, histidine Phosphates, phosphates, citric acid, citrates, carbonates, carbonates, and their pharmaceutically acceptable It is also one or more selected from the possible salts.

[0029] The concentration of the buffering agent is 1 to 100 mM, 1 to 70 mM, 1 to 50 mM, 1 Stone 40mM, 1 to 30mM, 1 to 25mM, 1 to 22mM, 1 to 20 mM, 5 to 100 mM, 5 to 70 mM, 5 to 50 mM, 5 to 40 mM, 5 to 30 mM, 5 to 25 mM, 5 to 22 mM, 5 to 20 mM, 10 mM or less 100mM, 10 to 70mM, 10 to 50mM, 10 to 40mM, 10 Stone 30mM, 10 to 25mM, 10 to 22mM, 10 to 20mM, 14 Stone 100mM, 14 to 70mM, 14 to 50mM, 14 to 40mM, 14 or 30 mM, 14 to 25 mM, 14 to 22 mM, 14 to 20 mM, 16 or 100 mM, 16 or 70 mM, 16 or 50 mM, 16 or 40 mM, 1 6 to 30 mM, 16 to 25 mM, 16 to 22 mM, or 16 to 20 mM M can also be, for example, 16mM, 17mM, 18mM, 19mM, or 20mM.

[0030] The aforementioned pharmaceutical formulation may also be surfactant-free. The aforementioned surfactant is non-ionic. It is also a nonionic surfactant. The aforementioned nonionic surfactants include polysorbate and poloxamer. The polysorbate is also a sorbitan ester of other fatty acids, or a mixture thereof. The products are polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80, or a mixture thereof. The poloxamer is also poloxamer 188.

[0031] The aforementioned pharmaceutical preparation is also a liquid. The aforementioned pharmaceutical preparation is for subcutaneous or intravenous injection. It is also for use. The aforementioned pharmaceutical preparation further comprises an aqueous carrier suitable for injection. Furthermore, the aqueous carrier is safe and non-toxic when administered to humans, and is pharmaceutically acceptable. These are substances that can be used, such as water, saline solution, intravenous solution, dextrose, or mixtures thereof. It is also an object.

[0032] The aforementioned pharmaceutical preparations may have an appropriate osmotic pressure range when administered by subcutaneous or intravenous injection. The osmotic pressure is, for example, 200 to 400 mOsm / kg, 200 to 350 mOsm / kg, 250 to 300 mOsm / kg, 250 to 290 mOsm / kg, 27 0 to 328 mOsm / kg, 250 to 269 mOsm / kg, or less than 328 mOsm / kg It is also 350 mOsm / kg. The osmotic pressure minimizes pain that may occur during administration. It can be appropriately adjusted for this purpose.

[0033] The aforementioned pharmaceutical formulation may have a viscosity within an appropriate range when administered by subcutaneous or intravenous injection. The viscosity, measured at room temperature of 25°C ± 3°C, is, for example, 0.5 to 100 cp, or 0. 5 to 90 cp, 0.5 to 80 cp, 0.5 to 70 cp, 0.5 to 60 c p, 0.5 to 50 cp, 0.5 to 40 cp, 0.5 to 30 cp, none of 0.5 The viscosity is 20 cp, 0.5 to 15 cp, or 0.5 to 10. It can be appropriately adjusted to minimize any pain that may occur during administration.

[0034] In one specific example, the pharmaceutical preparation is the anti-PD-1 antibody, for example, pembroliz The concentration of the mab antibody or its antigen-binding fragment is 5 to 300 mg / mL, 5 to 200 The concentration is mg / mL, 15 to 30 mg / mL, or 140 to 160 mg / mL. The stabilizers include sucrose, glucose, galactose, maltose, and protose. Trehalose, sorbitol, mannitol, arginine, lysine, proline, glycine Phenylalanine, tyrosine, tryptophan, its hydrate, its pharmaceutically acceptable A salt, or a mixture thereof, and the pH of the pharmaceutical preparation is 4.5 to 6.5. There are also others.

[0035] The stabilizers are sucrose, glucose, galactose, maltose, and protose. The stabilizer is trehalose, its hydrate, or a mixture thereof, and the concentration of the stabilizer is 1.0 Ishi 15.0% (w / v), 3.0 to 15.0% (w / v), 5.0 to 15.0 %(w / v), 7.0 to 15.0%(w / v), 1.0 to 10.0%(w / v) 3.0 to 10.0% (w / v), 5.0 to 10.0% (w / v), 7.0% (not present) 10.0% (w / v), 1.0 to 7.0% (w / v), 2.0 to 7.0% (w / v), 3.0 to 7.0% (w / v), 4.0 to 7.0% (w / v), 1.0 Stone 5.0% (w / v), 0.02 to 5.0% (w / v), 3.0 to 5.0% ( w / v), or 4.0 to 5.0% (w / v), 4.5 to 5.0% (w / v) Examples: approximately 4.7% (w / v), or 7.8 to 8.2% (w / v) (Example: approximately 7.8%) (w / v), approximately 7.9% (w / v), approximately 8% (w / v), approximately 8.1% (w / v), or approximately It is also 8.2% (w / v). The stabilizers are sorbitol, mannitol, and water. It is a compound or a mixture thereof, and the concentration of the stabilizer is 1.0 to 20.0 w / v%. For example, 1.0 to 15.0 w / v%, 1.0 to 10.0 w / v%, 2.5 to 10.0 w / v%, 3.0 to 10.0 w / v%, 3.5 to 10.0 w / v%, 4 0.0 to 10.0 w / v%, 1.0 to 8.0 w / v%, 2.5 to 8.0 w / v %, 3.0 to 8.0 w / v%, 3.5 to 8.0 w / v%, 4.0 to 8.0 w / v%, 1.0 to 6.0 w / v%, 2.5 to 6.0 w / v%, 3.0 to 6. 0 w / v%, 3.5 to 6.0 w / v%, 4.0 to 6.0 w / v%, 4.0 to The concentration is 5.5 w / v%, or 4.0 to 5.0 w / v%. The stabilizer is argy Nine, lysine, proline, glycine, phenylalanine, tyrosine, tryptophan, so The hydrate, a pharmaceutically acceptable salt thereof, or a mixture thereof, and the stabilizer The concentrations are 0.1 to 300.0 mM, 0.5 to 300.0 mM, and 1.0 to 30 0.0 mM, 5.0 to 300.0 mM, 10.0 to 300.0 mM, 25.0 mM Stone 300.0 mM, 30.0 to 300.0 mM, 50.0 to 300.0 mM, 80.0 to 300.0 mM, 100.0 to 300.0 mM, 120.0 to 3 0.0 mM, 0.1 to 250.0 mM, 0.5 to 250.0 mM, 1.0 mM (none) 250.0 mM, 5.0 to 250.0 mM, 10.0 to 250.0 mM, 25 0.0 to 250.0 mM, 30.0 to 250.0 mM, 50.0 to 250.0 mM mM, 80.0 to 250.0 mM, 100.0 to 250.0 mM, 120.0 mM Stone 250.0 mM, 0.1 to 200.0 mM, 0.5 to 200.0 mM, 1. 0 to 200.0 mM, 5.0 to 200.0 mM, 10.0 to 200.0 mM , 25.0 to 200.0 mM, 30.0 to 200.0 mM, 50.0 to 20 0.0 mM, 80.0 to 200.0 mM, 100.0 to 200.0 mM, 120 0.0 to 200.0 mM, 0.1 to 160.0 mM, 0.5 to 160.0 mM , 1.0 to 160.0 mM, 5.0 to 160.0 mM, 10.0 to 160. 0 mM, 25.0 to 160.0 mM, 30.0 to 160.0 mM, 50.0 mM or less 160.0 mM, 80.0 to 160.0 mM, 100.0 to 160.0 mM, 120.0 to 160.0 mM, 130.0 to 150.0 mM, 0.1 to 10 0.0 mM, 0.5 to 100.0 mM, 1.0 to 100.0 mM, 5.0 to 100.0 mM, 10.0 to 100.0 mM, 25.0 to 100.0 mM, 30 0.0 to 100.0 mM, 50.0 to 100.0 mM, 80.0 to 100.0 mM, 0.1 to 50.0 mM, 0.5 to 50.0 mM, 1.0 to 50.0 mM M, 5.0 to 50.0 mM, 10.0 to 50.0 mM, 25.0 to 50.0 mM, or 30.0 to 50.0 mM, 0.1 to 40.0 mM, 0.5 to 4 mM 0.0 mM, 1.0 to 40.0 mM, 5.0 to 40.0 mM, 10.0 to 4 0.0 mM, 25.0 to 40.0 mM, or 30.0 to 40.0 mM, 0.1 or 30.0 mM, 0.5 or 30.0 mM, 1.0 or 30.0 mM, 5.0 mM Stone 30.0 mM, 10.0 to 30.0 mM, 25.0 to 30.0 mM, 0.1 or 20.0 mM, 0.5 or 20.0 mM, 1.0 or 20.0 mM, 5.0 The concentrations are 20.0 mM, 10.0 to 20.0 mM, 0.1 to 10.0 mM, and 0.5 mM. The mineral content is 10.0 mM, 1.0 to 10.0 mM, or 5.0 to 10.0 mM. ru.

[0036] In the above specific example, the buffering agent is phosphoric acid, acetic acid, citric acid, succinic acid, carbonic acid, histidine It may also contain an alkali metal salt, or a pharmaceutically acceptable salt thereof. Alternatively, it may be a hydrochloride salt. The alkali metal may also be sodium or potassium.

[0037] In the above specific example, the concentration of the buffering agent is 1 to 100 mM, 1 to 70 mM, 1 to 50 mM, 1 to 40 mM, 1 to 30 mM, 1 to 25 mM, 1 to 22mM, 1 to 20mM, 5 to 100mM, 5 to 70mM, 5 to 50m M, 5 to 40 mM, 5 to 30 mM, 5 to 25 mM, 5 to 22 mM, 5 Stone 20mM, 10 to 100mM, 10 to 70mM, 10 to 50mM, 10 or 40 mM, 10 to 30 mM, 10 to 25 mM, 10 to 22 mM, 10 or 20 mM, 14 or 100 mM, 14 or 70 mM, 14 or 50 mM, 1 4 to 40 mM, 14 to 30 mM, 14 to 25 mM, 14 to 22 mM, 1 4 to 20 mM, 16 to 100 mM, 16 to 70 mM, 16 to 50 mM, 16 to 40 mM, 16 to 30 mM, 16 to 25 mM, 16 to 22 mM, Or 16 to 20 mM, for example, 16 mM, 17 mM, 18 mM, 19 mM or 2 It is also 0 mM.

[0038] In the pharmaceutical formulation of the present invention, the anti-PD-1 antibody, for example, pembrolizumab antibody Or, the antigen-binding fragment can be stabilized. The term "stabilization" is a reference to the previous Anti-PD-1 antibodies, such as pembrolizumab antibodies or their antigen-binding fragments, are administered before and after administration. , additional manufacturing processes, its physical stability during storage or preservation, chemical stability, and / Or it means substantially possessing biological activity. The physical stability, chemical stability Qualitative and / or biological activity can be evaluated using generally known methods.

[0039] In this specification, the stability of the anti-PD-1 antibody or its antigen-binding fragment is as follows: It also satisfies condition 1 or higher.

[0040] Stability is measured at a selected temperature for a selected period of time. For example, in one specific case, a stable formulation can be kept at 2°C to 8°C for 12 months. A formulation in which no significant changes are observed for a period of time or longer. In other specific examples, stable The formulation showed no significant changes at temperatures of 2°C to 8°C for 18 months or longer. It is a formulation that is not detected. In other specific examples, stable formulations are found at 23°C to 27°C. This refers to a formulation in which no significant changes are observed for three months or longer. Other specific examples In this case, the stable formulation can be stored at 23°C to 27°C for 6 months or longer. , a formulation in which no significant changes are observed. In other specific examples, a stable formulation is 23°C A formulation in which no significant change is observed for 12 months or longer at 27°C. In other specific examples, the stable formulation lasts for 18 months at 23°C to 27°C. A formulation in which no significant changes are observed for a period of time or longer. Stability related to antibody preparations The criteria are as follows: Measurements were taken using size exclusion chromatography (SE-HPLC). In cases where less than 10% of the antibody monomer is degraded, for example, less than 5% or less or less than 2.5%. Yes. The antibody potency is 60 to 140% of the control group or standard antibody, or 8%. It is between 0 and 120%. For example, low-millimeter-weight species (LMW) were measured by SE-HPLC. In some cases, the antibody may show a change of 10% or less, 5% or less, or 2.5% or less. For example, when high-molecular-weight species (HMW) are measured by SE-HPLC, less than 10% of the antibody, less than 5% It may also have a change of less than or equal to 2.5%. Furthermore, the concentration and pH of the preparation may be ± These also include changes of 10% or less, ±5% or less, or ±2.5% or less.

[0041] The aforementioned pharmaceutical preparations should be placed in a stability incubator at a temperature of 40±2°C and a relative humidity of 75±5%. When left for 4 weeks under these conditions, within the range of 10% or less, 5% or less, or 2.5% or less These are also substances that change HMW or pH.

[0042] The aforementioned pharmaceutical preparation is dispensed in a 2cc vial of type I glass material (Sc) in a quantity of 0.3 to 1 mL. Place the vial (manufactured by Hott) into the stirrer (manufactured by Heidolph) and stir at room temperature at 400 rpm. When stirred at PM for 72 hours, the odor was within the range of 10% or less, 5% or less, or 2.5% or less. This also means that the HMW or pH changes.

[0043] The pembrolizumab or its antigen-binding fragment still retains biological activity. If chemically stable within a predetermined time, the chemical It can maintain chemical stability. This chemical stability is achieved in the chemically modified form of Pembu. It can also be evaluated by detecting and quantifying the lorizumable. This chemical deformation is a change in size. This includes changes in shape or charge. The charge change is, for example, a charge resulting from deamidation. This also represents a change. The aforementioned size deformation was analyzed using size exclusion chromatography (SE-HPLC). Sodium dodecyl sulfate / polyacrylamide gel electrophoresis (SDS-PAGE) analysis Capillary electrophoresis of sodium dodecyl sulfate (CE-SDS) s-sodium dodecyl sulfate, analysis, and substrate-assisted laser desorption / ionization / time-of-flight mass Analysis (MALDI / TOF MS:matrix-assisted laser desorption / ionization / time- It can also be evaluated using (of-flight mass spectrometry). Furthermore, the charge change is ion Ion exchange chromatography (ICE) and image capillaries, etc. Also by electrofocusing (icIEF: imaged capillary isoelectric focusing) It is evaluated. Activity can be determined via PD-1 ligand binding analysis. PD- 1. Ligand binding analysis is enzyme-linked immunosorbent assay (ELISA). This can also be performed by an ELISA assay. This ELISA analysis shows that pembrolizumab is effective against PD-1 receptors. This measures the percentage of binding to Gandol. The pembrolizumab sample and ELIS are used. After reacting with the PD-1 ligand on substrate A, the degree of binding was measured by measuring the absorbance at 450 nm. This allows us to obtain the relative binding rate (%).

[0044] The aforementioned anti-PD-1 antibody, for example, pembrolizumab antibody or its antigen-binding fragment, is a drug The compound possesses biological activity within the pharmaceutical formulation. This biological activity is, for example, obtained through pharmaceutical formulation. Within the drug, the biological activity of the anti-PD-1 antibody or its antigen-binding fragment is determined by the pharmaceutical manufacturing process. Within approximately 30%, 20%, or 10% of the biological activity shown at the time of manufacture of the agent (or If it is within the analytical error range, it possesses biological activity. The said biological activity is, for example, It can also be determined by antigen-binding analysis.

[0045] The degree of stabilization depends on temperature stress, for example, freezing at 40°C for 1 to 4 weeks. Thawing stress, for example, five repetitions of a cycle of freezing at -70°C and thawing at room temperature, or Agitation stress, for example, in a stirrer, applying a rotational force of 400 rpm for 72 hours, and size reduction High-performance liquid chromatography (SE-HPLC: size-exclusion high performance liquid chromatography) Using id chromatography, % HMW, % monomer and / or % LMW are measured. This can be evaluated by... Compared to Truda (Keytruda(R)), it has an equivalent or even lower Δ% HMW value. It may have a Δ% LMW value or a Δ% monomer value.

[0046] The stable pharmaceutical formulations provided herein have an antibody content of 25 mg / ml. (pH 5.5), 0.3 to 1 mL of the preparation, into a 2 cc vial of type I glass material (Sc Stored in a container (manufactured by HOTT) at 40°C for 4 weeks, and measured using a standard SEC (Percentage of HM) % HM The change in W, i.e., the % HMW value after 4 weeks and the % HMW value at week 0, is 10.0% or less, 5 It is either 0% or less, or 2.5%.

[0047] Another embodiment provides a method for treating cancer with the aforementioned pharmaceutical preparation. Therefore, as stated above, the method of treating the aforementioned cancer is that pharmaceutical preparations are effective in treating cancer. It also includes a step of administering a certain amount to an individual. The individual can be a human.

[0048] In the above method, the term "cancer" is defined as a term typically characterized by upward-regulated cell growth. It refers to or describes pathological conditions in mammals. The aforementioned cancer is This includes, but is not limited to, carcinomas, lymphomas, leukemias, blastomas, and sarcomas. No. The aforementioned cancers include, for example, squamous cell carcinoma, myeloma, small cell lung cancer, non-small cell lung cancer, glioma, Hodgkin lymphoma, non-Hodgkin lymphoma, gastrointestinal cancer or gastrointestinal tract cancer, kidney cancer, ovarian cancer, liver cancer Cancer, lymphoblastic leukemia, lymphocytic leukemia, colorectal cancer, endometrial cancer, kidney cancer, prostate cancer Cancer, thyroid cancer, melanoma, chondrosarcoma, neuroblastoma, pancreatic and intestinal cancer, glioblastoma multiforme, cervix Cancer, brain cancer, stomach cancer, bladder cancer, hepatocellular carcinoma, breast cancer, colon carcinoma, Merkel cell carcinoma, high-frequency satellite This includes dysinusitis, esophageal cancer, urothelial carcinoma, primary mediastinal giant B-cell lymphoma, and head and neck cancer. It is also a thing.

[0049] Another embodiment involves the step of adding a stabilizer to a solvent to produce a mixed solution; and the mixed solution is subjected to Adding a PD-1 antibody or its antigen-binding fragment, or adding an anti-PD-1 antibody to the solvent. Add the body or its antigen-binding fragment to prepare an anti-PD-1 antibody or its antigen-binding fragment solution. A stable pharmaceutical formulation is produced, comprising the steps of: 1. preparing the solution; and 2. adding a stabilizer to the solution. The present invention provides a method in which the manufacturing step is carried out without the addition of a buffering agent.

[0050] In the above method, the solvent is also an aqueous solvent, such as water or saline. The above method involves adding the anti-PD-1 antibody or its antigen-binding fragment to a mixed solution, and then adding the following: This also includes the step of adding surfactants.

[0051] In terms or elements referred to in the aforementioned pharmaceutical preparation, the production of the requested pharmaceutical preparation The points mentioned in the explanation regarding the manufacturing method are related to the pharmaceutical manufacturing requested in the aforementioned section. It is understood that this refers to the points mentioned in the explanation regarding the drug. [Effects of the Invention]

[0052] According to one embodiment of a stable anti-PD-1 antibody pharmaceutical preparation, even without containing surfactants... Anti-PD-1 antibodies can be maintained to ensure stability.

[0053] According to one embodiment of a method for treating cancer in an individual, it is possible to efficiently treat cancer in the individual. It is possible.

[0054] According to one embodiment of a method for producing a stable anti-PD-1 antibody pharmaceutical preparation, This allows for the efficient manufacture of anti-PD-1 antibody pharmaceutical formulations. [Brief explanation of the drawing]

[0055] [Figure 1] This figure shows the Tag values ​​for buffer-free or histidine buffer and surfactant content in other formulations. [Figure 2] This figure shows the HMW content of formulations with different buffer and PS80 content after being subjected to temperature stress for 4 weeks. [Modes for carrying out the invention]

[0056] The present invention will be described in more detail below with reference to the following examples. However, the following examples The examples provided are for illustrative purposes only and do not limit the scope of the present invention. It is not something that can be done.

[0057] Materials and methods 1. Size exclusion chromatography (SEC) The purity of the sample was examined by size exclusion chromatography. In the graph, antibody monomers and high molecular weight species (HMW) are used. The percentages of ) and low molecular weight species (LMW) are determined. In size exclusion chromatography, the LMW elutes more slowly than the HMW. The presence of HMW indicates protein aggregation, and the presence of LMW indicates protein This shows a crystalline fragment.

[0058] 2.Dynamic light scattering (DLS) measurement method Aggregates in the sample were examined using dynamic light scattering measurement. Specifically, each Each sample was diluted with buffer and loaded into the wells of a 96-well plate. The aforementioned plate was modified by DynoPro (R) Plate Reader TM II (Wyatt Technology equipment) The sample was loaded onto the vehicle. The temperature of the sample was increased at a rate of 0.15°C / min in the range of 25°C to 70°C. While measuring the size of aggregates in pharmaceutical formulations via dynamic light scattering (DLS), It was determined. The stability evaluation involves measuring the temperature at which the size of the aggregate changes, T agg A higher value indicates greater stability.

[0059] 3. Manufacturing of pharmaceutical preparations Each pharmaceutical preparation listed in Table 1 was manufactured as described below and used in the following examples. Ta.

[0060] First, in the composition of each pharmaceutical preparation listed in Table 1, pembrolizumab and surfactant A buffer solution was prepared by adding a buffering agent (without the actionant) and a stabilizer to sterile distilled water. Brolizumab administered via a dialysis cassette (Slide-A-Lyzer cassette; Thermo Fisher Scientific) After placing it in the container, place it in a beaker containing the solution of each composition listed in Table 1, and perform dialysis. Finally, the existing pembrolizumab solution was replaced with the buffer solution. Lastly, a surfactant was added. In the case of a formulation, the pembrolizumab solution is mixed with the prepared buffer solution containing the surfactant The agent PS80 was added to a concentration of 1x. Then, each solution was used to treat pembroliz The mab concentration was adjusted to a final 25 mg / ml.

[0061] [Table 1]

[0062] In Table 1, in groups 2 to 4, the surfactant is PS80, i.e., polysorbate. This shows a rubate of 80.

[0063] Example 1: Buffer and surfactant content stabilizes pembrolizumab-containing pharmaceutical formulations. Effects on sex In this embodiment, the buffer and surfactant content are pembrolizumab-containing pharmaceutical The effect on the stability of the formulation was confirmed. Specifically, 1A, 1B, 1C, 2A, 2B, 2 For the C, 3A, 3B, 3C, 4A, 4B, and 4C formulations, the T value was measured by the DLS measurement method. agg The results are shown in Table 2 and Figure 1. Table 2 shows the content of the surfactant PS80 and histidine buffer, as well as the composition of other formulations and the T measurement values related thereto.

[0064] It is a table. Figure 1 is a drawing showing the content of the surfactant and histidine buffer, and the T values related to other formulations. As shown in Table 2 and Figure 1, the T value of the formulation that does not contain the surfactant PS80 or contains 0.02% is higher than that of the formulation that contains the surfactant PS80 at 0.10% or 0.20%. That is, formulations containing a low content of PS80 less than 0.10%, namely 1A, 1B, 1C, 2A, 2B, and 2C, show aggregation at a higher temperature compared to formulations containing a high content of PS80 of 0.10% or more, namely 3A, 3B, 3C, 4A, 4B, and 4C. That is, formulations containing a low content of PS80 less than 0.10% are shown to be more stable than formulations containing a high content of PS80 of 0.10% or more. On the other hand, when the concentration of PS80 is less than 0.10%, the content of histidine does not have a significant impact on the change in T. agg It showed the measured values. Figure 1 is a drawing showing the content of the surfactant and histidine buffer, and the T values related to other formulations. agg It is a drawing showing the values.

[0065] <000064​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​Furthermore, in a formulation containing 20 mM histidine buffer, a formulation containing PS80, that is, Chi, 2B, 3B and 4B T agg Compared to the value, formulations that do not contain PS80, i.e., 1B's T agg The value was the highest. On the other hand, the odor of the preparation containing 40 mM histidine buffer Therefore, a formulation containing 0.02% PS80, i.e., 2C Tagg The values ​​are 1C, 3C and 4C's T agg It was higher than the stated value.

[0068] Example 2: Buffer and surfactant content stabilizes pembrolizumab-containing pharmaceutical formulations. Effects on sex In this embodiment, the buffer and surfactant content are pembrolizumab-containing pharmaceutical The effect on the stability of the formulation was confirmed. Specifically, 1A, 1B, 1C, 2A, 2B, 2 For formulations C, 3A, 3B, 3C, 4A, 4B, and 4C, after applying temperature stress, SE The purity of the sample was measured via C.

[0069] The aforementioned temperature stress is applied by placing 0.3 mL of each of the formulations into a 2 cc bag of Type I glass material. Place the vial (manufactured by Schott) and then place the vial in a stable incubator (manufactured by JEIO TECH). The vial was exposed to a temperature stress condition of 40°C for 4 weeks. Specifically, the vial was subjected to the stable The samples were placed in a constant-temperature incubator and kept at a temperature of 40±2°C and a relative humidity of 75±5% for 4 weeks. SEC analysis was performed on the stored formulations as described above.

[0070] The results are shown in Table 3 and Figure 2. Table 3 shows the results for different buffer and PS80 content levels. The composition of the formulation and the purity of the formulation subjected to 4 weeks of temperature stress are shown in terms of HMW content. This is a table. Figure 2 shows the results of 4 weeks of temperature storage for formulations with different buffer and PS80 content. This diagram shows the HMW content of the formulation after adding the sulfate.

[0071] [Table 3]

[0072] As shown in Table 3 and Figure 2, in the buffer-free composition, the manufacturing process includes PS80. Compared to the △% HMW values ​​of agents 2A, 3A, and 4A, the products that do not contain PS80 The agent, namely 1A, had the lowest △% HMW value. It contained 20 mM histidine buffer. In formulations containing PS80, i.e., formulations 2B, 3B and 4B have a △% HMW value. In comparison, the formulation that did not contain PS80, i.e., 1B, had the lowest △% HMW value. Furthermore, in a formulation containing 40 mM histidine buffer, a formulation containing PS80, that is, Compared to the △% HMW values ​​of 2C, 3C, and 4C, preparations that do not contain PS80, that is, The △% HMW value of 1C was the lowest. This is because it does not contain the surfactant PS80. Group 1 formulations (1A, 1B, and 1C) are even more effective than Group 2, 3, and 4 formulations containing PS80. This indicates stability.

[0073] Furthermore, the pH of the formulations stored under stress conditions for 4 weeks was measured. Table 4 shows the results at 40°C. This table shows the results of pH measurements for samples left under temperature stress conditions for 4 weeks. .

[0074] [Table 4]

[0075] As shown in Table 4, formulations 1A, 1B and 1 do not contain polysorbate 80. The pH of C is 0.02% to 0.20%. Formulations 2A, 2B, 2C, and 3A contain PS80. No significant difference was observed compared to the pH of 3B, 3C, 4A, 4B, and 4C. Surface activity In dosage forms that do not contain surfactants, pH stability is similar to that of dosage forms that contain surfactants. We confirmed that this would be maintained.

Claims

1. (a) an anti-PD-1 antibody or its antigen-binding fragment, (b) Stabilizer and, (c) A buffering agent, A stable anti-PD-1 antibody drug that does not contain surfactants and has a pH of approximately 4.5 to 6.

5. Medical preparations.

2. The pharmaceutical formulation according to claim 1, wherein the anti-PD-1 antibody is a pembrolizumab antibody. 。

3. The concentration of the anti-PD-1 antibody or its antigen-binding fragment is approximately 5 to 300 mg / ml. , the pharmaceutical preparation according to claim 1.

4. The concentration of the pembrolizumab antibody or its antigen-binding fragment is approximately 10 to 165 mg / m². The pharmaceutical preparation according to claim 1, wherein L.

5. The concentration of the anti-PD-1 antibody or its antigen-binding fragment is approximately 25 or approximately 150 mg / m². The pharmaceutical preparation according to claim 1, wherein L.

6. The stabilizer is a polyol, an amino acid, or a pharmaceutically acceptable salt thereof. The pharmaceutical preparation according to claim 1, wherein is a mixture thereof.

7. The aforementioned polyols are sorbitol, sucrose, trehalose, mannose, and maltose. The pharmaceutical preparation according to claim 6, which is sucrose, mannitol, or a mixture thereof.

8. The polyol is sorbitol, sucrose, trehalose, or a mixture thereof. The pharmaceutical preparation according to claim 6.

9. The aforementioned amino acids are glycine, proline, phenylalanine, tyrosine, and tryptophan. The claim is that lysine, arginine, a pharmaceutically acceptable salt thereof, or a mixture thereof. The pharmaceutical preparation described in 6.

10. The stabilizer is approximately 1.0 to 15.0 w / v% sugar, approximately 1.0 to 20.0 w / v% sugar Alcohol, approximately 0.1–300 mM amino acids, or approximately 1.0–300.0 mM metals A pharmaceutical preparation according to claim 1, which is a salt.

11. The pharmaceutical formulation according to claim 1, wherein the surfactant is a nonionic surfactant.

12. The surfactants include polysorbates, poloxamers, and sorbitan esters of other fatty acids. The pharmaceutical preparation according to claim 11, which is a mixture thereof.

13. The polysorbate is polysorbate 20, polysorbate 80, or a mixture thereof. A pharmaceutical preparation according to claim 12, which is a compound.

14. The buffering agents include histidine, phosphoric acid, maleic acid, tartaric acid, succinic acid, citric acid, and acetic acid. The claim 1 is a carbonic acid, a pharmaceutically acceptable salt thereof, or a mixture thereof. Pharmaceutical preparations.

15. The pharmaceutical formulation according to claim 1, wherein the concentration of the buffering agent is approximately 5 mM to less than 40 mM. 。

16. The concentration of the anti-PD-1 antibody or its antigen-binding fragment is approximately 5 to 300 mg / mL. The stabilizer is approximately 1.0 to 15.0 w / v% sucrose, trehalose, and its hydrated Substances or mixtures thereof, approximately 1.0–20.0 w / v% sorbitol, mannitol , its hydrate or mixture thereof, or about 0.1 to 300.0 mM arginine, lysine , proline, glycine, phenylalanine, tyrosine, tryptophan, their pharmaceuticals The buffering agent is an acceptable salt, or a mixture thereof, and is approximately 5 mM to 40 mM. Histidine, phosphoric acid, maleic acid, tartaric acid, succinic acid, citric acid, acetic acid, carbonic acid, and The pharmaceutically acceptable salts of the same, or mixtures thereof, as described in claim 1. formulation.

17. The concentration of the anti-PD-1 antibody or its antigen-binding fragment is approximately 5 to 200 mg / mL. , the pharmaceutical preparation according to claim 16.

18. The concentration of the anti-PD-1 antibody or its antigen-binding fragment is approximately 15 to 30 mg / ml, The pharmaceutical preparation according to claim 16, wherein the concentration is approximately 140 to 160 mg / mL.

19. The pharmaceutical preparation according to claim 16, which does not contain the nonionic surfactant.

20. The aforementioned nonionic surfactant is polysorbate, poloxamer, or sorbita of other fatty acids. A pharmaceutical preparation according to claim 19, which is an ester or a mixture thereof.

21. The step of administering to an individual an amount of the pharmaceutical formulation according to claim 1 that is effective in treating cancer, Methods of treating cancer in the body.

22. A step of preparing a mixed solution by adding a stabilizer and a buffer to the solvent, The step of adding pembrolizumab antibody or its antigen-binding fragment to the mixed solution, or Add pembrolizumab antibody or its antigen-binding fragment to the solvent, and pembrolizumab antibody or the step of producing the antigen-binding fragment solution thereof, A stable anti-PD-1 antibody drug comprising the step of adding a stabilizer and a buffer to the aforementioned solution. A method for manufacturing pharmaceutical preparations.

Images